In the rat, the aging hippocampus loses neurons, and cumulative exposure to glucocorticoids (GCs), the adrenal stress hormone, plays a major role in such loss; it is prevented by decreasing lifetime GC exposure, while GCs and/or stress accelerate senescent neuron loss. My work suggests that GCs disrupt energy metabolism and comprise the ability of neurons to survive metabolic challenges; thus, excitotoxins, antimetabolites and hypoxia-ischemia are all more damaging to the hippocampus in rats exposed to elevated GC concentrations and are less so in adrenalectomized rats. A similar exacerbation of toxicity of these insults by GCs occurs in primary hippocampal cultures and is GC receptor-mediated. These observations have lead to the development of pharmacological and behavioral interventions that protect the hippocampus from GCs after such insults and during aging, and decrease cognitive impairments arising from hippocampal damage. Of human relevance, we find that chronic stress also damages the primate hippocampus. Despite these advances, it is still not clear how GCs endanger hippocampal neurons. Part I: We have found that GCs inhibit 30% of glucose transport into cultured hippocampal neurons and glia. We will 1) test whether hippocampal glucose utilization in vivo is sensitive to physiological changes in GC concentrations; 2) determine the molecular mechanisms underlying the effect; 3) assess the energetic consequences of a 30% inhibition of glucose transport for hippocampal neurons by measuring phosphocreatine in GC- treated cultures under basal and metabolically-challenged conditions; 4) test whether the elevated GC concentrations typical of aged rats inhibits hippocampal glucose utilization. Part II: We have found that GCs increase the activity of glutamine synthetase in the adult hippocampus. This astrocytic enzyme is the rate-limiting step in a shuttle that provides glutamine to neurons for conversion to the excitotoxin glutamate. 1) Is this GC effect physiological? 2) Do the elevated GC concentrations of the aged rat cause an increase in glutamine synthetase activity? Part III: Glutamate (and other excitatory amino acids -- EAAs) appears to mediate various neurological insults to the hippocampus. Both energy depletion and increased glutamine synthetase activity enhance extracellular EAA concentrations. Thus GCs, via their effects on glucose transport and glutamine synthetase, might do the same; our data suggest that is the case. 1) Do GCs increase extracellular EAA concentrations basally or during metabolic challenges? 2) If so, do GCs enhance EAA release or impair their uptake, and if the latter, is this a neuronal or glial effect? 3) Are these effects attributable to GC effects on glucose uptake and/or on glutamine synthetase? 4) Is this GC effect relevant to the aging hippocampus? Part IV: EAAs ultimately damage neurons by increasing free cytosolic calcium concentrations. Our data show that GCs do the same. 1) Does this occur both basally and during metabolic challenges? 2) Do GCs enhance calcium influx or release from intracellular stores, or diminish efflux? 3) Do these GC effects arise from their inhibition of glucose transport? 4) Do GCs effect calcium trafficking in the aged hippocampus?